Leukodystrophies disrupt the growth/maintenance of the myelin sheath, leading to progressive degeneration of white matter and early death. Krabbe disease, a genetically based leukodystrophy detected chiefly in infants, is due to a deficiency of ?-galactosylceramidase (GALC), resulting in the accumulation of the toxic metabolite galactosyl-sphingosine, known as psychosine. Our previous findings using in vitro cell systems mimicking psychosine toxicity in neurons and oligodendrocytes, as well as in the twitcher mouse, the naturally occurring mouse model of Krabbe disease, identified downstream effects of psychosine such as lipid raft alterations, deficits in axonal transport, and deregulation of the IGF-1-Akt pathway. These observations add to the current view of Krabbe disease as a demyelinating condition with strong neuroinflammation. The intimate interaction between myelin and axons prompted us to propose that a more efficacious treatment of this disease will require a global approach, where gene correction of GALC deficiency needs to be complemented with approaches to reduce neuroinflammation and to increase the protection of neurons, and axons. Therefore, our goal for this cycle is to optimize a new combination of therapies using state-of-the-art adeno-associated viruses for global expression of therapeutic GALC in the nervous system of the twitcher mouse, in combination with hematopoietic replacement, and small molecule-based neuropharmacology to reduce neuroinflammation, cell death, and neurodegeneration. This project delivers an unparalleled opportunity to advance our understanding of Krabbe disease, and to pre-clinically test new combined therapies, with the goal of formulating safer and more powerful treatments for affected Krabbe children.